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Senescence and aging: the critical roles of p53

Abstract

p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53’s impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.

Introduction

Senescence represents a stress response in which cells withdraw from the cell cycle and lose the capability to proliferate in response to growth factors or mitogens.1, 2 Senescent cells show very distinctive changes in morphology, acquiring a typical flat and enlarged shape and increase expression of recognized biomarkers of senescence, including staining for β-galactosidase at pH of 6.0 (senescence-associated-β-gal or SA-β-gal), decreased replicative capacity, increased expression of p53, p21, p16 and other cyclin-dependent kinase inhibitors, such as p27 and p15. Finally, accumulation of transcriptionally inactive heterochromatic structure (senescence-associated heterochromatic foci or SAHF) has been reported, particularly in the promoters of E2F-target genes.2, 3, 4

Initially thought to be a cell culture artifact, senescence has been more recently observed in vivo in cancer lesions and during physiological aging.3, 5, 6, 7, 8, 9, 10 Hence, recently, increasing interest has focused on senescence as a novel approach in cancer therapy, because of its inherent property to suppress cell proliferation, senescence may protect against cancer onset.2 Intriguingly, senescence is also intimately related to aging as both shared ability to limit lifespan. The constant regeneration of somatic tissues leads to accumulation of senescent cells, which limits tissue renewal, perturbs normal tissue homeostasis and ultimately elicits aging. Recent findings have established a causal role between senescence and aging: selective killing of p16-positive senescent cells in vivo ameliorates aging-related features in a mouse model of progeroid syndrome.8, 11

Senescence has been classically viewed as a state of permanent growth arrest, during which cells are unable to re-enter the cell cycle. Although this concept is still widely accepted, recent studies have provided evidence that under certain conditions this cellular status is reversible. In fact, stable suppression or even more subtle changes in p53 expression in senescent fibroblasts lead to rapid cell-cycle re-entry and immortalization, indicating that both initiation and maintenance of senescence are p53 dependent,12, 13, 14, 15 as discussed later in more detail. Regardless, senescence is functional to both tumor suppression and organismal aging, which means that p53 ability to regulate both processes may heavily rely on its fundamental role in eliciting cellular senescence.

Molecular mechanisms in senescence and aging

The senescence pathway can be triggered by multiple mechanisms. Originally, it was associated with replication exhaustion at the end of the cellular lifespan, a process currently defined as replicative senescence. Replicative senescence results from a combination of events that include the progressive erosion of telomeres during cell proliferation. This phenomenon can lead to critically short telomeres that are sensed by the cells as double-strand breaks. Double-strand breaks trigger the DNA damage response (DDR), a signaling cascade centered around the ataxia teleangectasia-mutated (ATM) kinase that activates p53 to elicit cell-cycle arrest and to execute senescence.16, 17, 18, 19, 20 Ectopic expression of telomerase, the enzyme responsible for telomere stabilization, circumvents replicative senescence in human cells,21 and stabilization of telomeres is essential for tumor progression. Telomeres are also important during aging. In humans, a positive correlation between telomere length and longevity has been suggested.20, 22, 23 In addition, a mouse model with depletion of telomerase shows several signs of accelerated aging, including anemia, kyphosis, osteoporosis, glucose intolerance, alopecia and hair graying.24, 25, 26 Here, a crucial event points to a progressive loss of the stem cell reservoir in these animals through induction of apoptosis and senescence. These phenotypes correlate with genomic instability and activation of p53,27 and genetic ablation of p53 ameliorates symptoms in mice with critically short telomeres.28 Thus telomere erosion links p53 to both senescence and aging.

Relevant for tumorigenesis, persistent oncogenic signaling is another important trigger that activates a powerful senescence response,29 known as oncogene-induced senescence (OIS). This process, indeed, prevents cellular transformation. Oncogenic H-Ras and, more generally, activation of oncogenes trigger hyperproliferation. Enforced DNA replication results in DDR followed by activation of senescence pathways, which must be overcome for transformation to occur. This process fails in cells that lack ATM activity or when cells cannot sense DNA damage or transduce DDR signals to p53.29

A major determinant of senescence, at the molecular level, is the intracellular accumulation of oxidative damage triggered by reactive oxygen species (ROS).2, 22, 30, 31, 32, 33, 34 ROS are generally small, short-lived and highly reactive molecules (for example, oxygen anions, superoxide and hydroxyl radicals, and peroxides) formed by partial reduction of oxygen, which, if not detoxified promptly by antioxidant agents, can oxidize macromolecules and damage organelles (Figure 1). Oxidation of DNA causes base modifications (that is, mutations) leading to various pathologies in humans, such as cancer, whereas oxidized proteins tend to form aggregates resulting in diverse neurodegenerative pathologies. ROS are also involved in aging as oxidative damage to various constituents of the cell may limit lifespan.35 In this regard, as mitochondria are the major source of ROS (Figure 1), a ‘mitochondrial free radical theory of aging’ has been postulated, arguing that mitochondrial-generated oxygen radicals cause widespread oxidative damage, eventually resulting in aging.36, 37 ROS enhance senescence and aging, inducing toxicity, into a feed-forward cycle: ROS cause damage to mitochondrial constituents, and, subsequently, damaged mitochondria produce more ROS.35, 38, 39, 40 The senescence–ROS correlation has attracted great interest, prompted by studies in several organisms, in which a negative relationship between mitochondrial ROS production and lifespan has been found.41, 42 Moreover, senescence and aging are associated with an increase in the levels of oxidative-damaged proteins, lipids and DNA,43, 44, 45 consequently to ROS-mediated damage to macromolecules such as proteins, nucleic acids and lipids. Mitochondrial-generated ROS have also been involved in OIS: Ras-driven senescence is associated with the accumulation of dysfunctional mitochondria, a sharp rise in ROS and a drop in ATP levels.46 Accordingly, chemical or genetic inhibition of the electron transport chain suffices in inducing senescence in human fibroblasts.46

Figure 1
figure1

Mitochondrial ROS. (a) A schematic model of ROS generation in the mitochondria. Superoxide (O2) generated by the respiratory chain is mostly released to the matrix at complex I and the IMS at complex III. O2 can naturally dismute to hydrogen peroxide (H2O2) or is enzymatically dismuted by matrix MnSOD or Cu/ZnSOD in the IMS or cytosol. H2O2 is detoxified in the matrix by catalase, the thioredoxin/thioredoxin peroxidase system (TPx), or the glutathione/glutathione peroxidase system (GPx). Alternately, H2O2 can react with metal ions to generate the highly reactive hydroxyl radical (·OH) via Fenton chemistry. O2 is not membrane permeable but can pass through ion channels (solid lines), whereas H2O2 can pass freely through membranes. (b) ROS can have both endogenous or exogenous sources. The overall balance in ROS cellular content is the result of ROS production and removal from specialized scavenging enzymes.

Mechanistically, senescence relies on two main molecular pathways: p53–p21 (discussed later) and p16INK4A-Rb. p16, a cyclin/cdk inhibitor, prevents phosphorylation of Rb by cyclin/cdk complexes. Hypophosphorylated Rb halts cell proliferation by inhibitory binding to E2Fs transcription factors, thus preventing them from stimulating transcription of genes involved in cellular proliferation and DNA replication.17 In this context, p16-Rb axis is pivotal to the establishment of cell-cycle arrest. During OIS, suppression of Rb abolishes the establishment of a proper senescent phenotype, but it is not sufficient to overcome cell-cycle arrest; this depends on the concomitant p53-dependent cell-cycle arrest.47

P53 in senescence and aging

p53 is a tetrameric transcription factor heavily regulated by posttranscriptional modifications.48, 49, 50, 51, 52 It is regarded as one of the most powerful tumor suppressor genes owing to its ability to halt cell proliferation and induce apoptosis and its activity is pivotal to successful traditional chemotherapy, as many DNA-damage-inducing drugs target tumors via p53-mediated apoptosis.49, 53, 54, 55 Consequently, p53 is mutated or lost in the vast majority of human cancers and considerable effort is focused on recovering its function in anticancer therapy.56, 57, 58, 59, 60, 61

p53 is clearly involved in cancer, but the existence of p53 in short-living organisms that do not develop cancers, such as flies and worms, suggests that tumor suppression is not its only and, probably, original function. Indeed, recent studies have shown that p53 influences development,62, 63 reproduction,64 metabolism65 and longevity.

The first evidence linking p53 to aging arose from the analysis of a mutant mouse model: in the attempt to develop a knock-in (KI) of p53, Tyson and colleagues obtained an aberrant serendipitous truncation of the N-terminal portion of the gene. The truncated mutant proteins showed a robust constitutive p53 activity and the mutant mice presented an array of aging-related features and severely reduced lifespan. In 2004, Scrable’s group produced a transgenic mouse model overexpressing the truncated ΔNp53 or p44 isoform of p53.66, 67 This mouse showed a striking defect in growth with associated reduced lifespan and accelerated aging. Interestingly, p44 overexpression resulted in hyperactive p53 and increased IGF signaling, a master regulator of aging.68 Recently, a KI mouse model of p53 was developed in order to mimic constitutive phosphorylation (that is, activation) of p53. This mouse model showed striking aging features, which seemed to result from widespread apoptosis affecting the stem cell compartments of several organs, hence compromising tissue self-renewal.69 PUMA is a proapoptotic protein and a well-characterized p53 target that exerts a fundamental role in induction of apoptosis and survival of stem cells: notably depletion of PUMA in the context of p53 mutations rescued the stem cell loss and ameliorated the aging phenotype.69 Thus, widespread apoptosis of stem cells may underline p53-mediated aging phenotype, possibility in agreement with studies highlighting an ‘aging’ process affecting stem cells.70 Although the mechanisms underlining these phenotypes are still unclear, these results led to the notion that excessive p53 activity compromises healthy aging. On the other hand, whether lack or reduced p53 activity affects lifespan has been difficult to assess, owing to the severe tumor phenotype that accompanies loss of p53.71 Nonetheless, recently developed in vivo models have shed light on the issue. A fundamental residue in p53 is Serine 15 (Ser-15) (ser-18 in mouse): phosphorylation of Ser-15 by ATM activates p53 in response to DNA damage. In 2006, Armata and colleagues analyzed the phenotype of KI mice where Ser-18 of p53 was replaced with non-phosphorylable alanine. These mice developed signs of accelerated aging, indicating that physiological p53 activity may preserve tissues from aging-related damage.72, 73 The super-arf/p53 mouse model, developed by Serrano’s group, provided an additional striking support to the anti-aging activity of p53. These transgenic mice bear long genomic sequence of p53 and p19arf, allowing their increased expression (owing to increased copy number, up to 4n), but maintaining endogenous regulation (as the regulatory region of the loci are preserved). In these circumstances, the authors noted an increase in lifespan and an overall improvement of the aging-related health decline.74 Although p19arf may act independently of p53, it is worth remembering that it does increase p53 activity preventing MDM2-mediated p53 proteasomal degradation.75 Overall, these findings suggest that loss of p53 is detrimental to aging.

In summary, the model that is emerging is an intensity-based model: physiological p53 activity prevents from cancer and protects from aging, whereas unrestrained and excessive p53 activation still protects from cancer, but is detrimental to healthy aging.

Induction of p53 is pivotal for the establishment of senescence, mainly following its activation by the DDR.76, 77 Indeed, depletion of p53 or abrogation of the upstream DDR signaling is sufficient to impair OIS.29 Several p53-targets and regulators have been linked to induction of senescence, including microRNAs,22, 78, 79 but the molecular mechanisms are still elusive. One of the most well-established p53-target genes, CDKN1A/p21, has been proved to be upregulated during replicative senescence.80, 81, 82, 83 p21 has been among the first identified downstream targets of p53, and it is an essential mediator of p53-dependent cell-cycle arrest. p21-depleted mouse embryonic fibroblasts are unable to undergo p53-dependent G1 arrest after DNA damage.84 The obvious dependency of p53 on p21 for the induction of cell-cycle arrest and the established role of p21 as inhibitor of proliferation suggest a crucial role for this gene in the induction of p53-dependent senescence (Figure 2). Indeed, lack of p21 abrogates senescence in several settings.85, 86, 87

Figure 2
figure2

Senescence regulation by p53. Several posttranslational modifications regulate p53 activity. Stimuli that activate the DDR, lead to active p53 via ATM-mediated phosphorylation. Active p53 triggers expression of pro-senescence targets such as p21, responsible for G1 cell-cycle arrest and E2F7, pivotal in repression of mitotic genes. In addition, p53 controls other pathways linked to aging, including ROS generation and mTOR. In this regard, while steady-state levels of p53 are able to dampen ROS and limit oxidative damage, active p53 elevates intracellular ROS, which participate in its proapoptotic and pro-senescent activities. Overall, the physiological role of p53-mediated regulation of ROS in senescence and aging is still unclear.

Nonetheless, although p21 contributes to the growth arrest of senescent cells, it is unlikely to be solely responsible for the complex and paramount changes underpinning senescence and, even more, aging. Moreover, p53 regulates a plethora of target genes affecting several physiological and metabolic pathways, all heavily involved in regulation of aging and establishment of senescence.88 Here, we review several of these pathways and discuss their potential implication in p53-induced senescence and p53-regulated aging (Figure 2).

p53 and E2F7

In agreement with the idea that p21 is not sufficient to explain the essential need for p53 in the establishment of senescence, two recent papers have described E2F7 as a new p53 target involved in cell-cycle arrest and senescence.47, 89 In particular, Aksoi and colleagues, in Scott Lowe’s laboratory, showed that E2F7 is upregulated in a p53-dependent fashion during proliferative as well as OIS. This gene is an atypical member of the E2F-family of transcription factors, as, unlike canonical E2Fs, it does not heterodimerize with DP1 proteins,90, 91 but binds DNA as a monomer and promotes repression of several E2F target genes, including E2F1. Moreover, many genes essential for mitosis, such as cyclin A, cyclin B and cdc2/cdk1, are repressed in senescent cells in a E2F7-dependent way. Hence, functionally, E2F7 arrests cell-cycle progression at the mitotic phase. This may have some important implications for tumorigenesis, explaining an apparent conundrum. In fact, both p53 and Rb are necessary for a full establishment of senescence. But, whereas p53-depleted cells are immortalized and readily transformed by exogenous oncogenic Ras alone, Rb-depleted cells, despite failing to undergo proper senescent arrest, are not immortalized and expression of Ras is not sufficient for their transformation and does not endow them with tumorigenic capability.92 Aksoi and colleagues demonstrate that p53-mediated upregulation of E2F7 is potentially responsible for this difference. In fact, concomitant inactivation of both Rb and E2F7 immortalizes cells and allows Ras-mediated cellular transformation.47

p53 and mTOR

The kinase mechanistic target of rapamycin (mTOR), previously known as mammalian TOR, is at the interface between growth and starvation. When nutrients are available, mTOR is active and promotes organism growth and anabolism. Conversely, in the case of nutrient depletion, mTOR is promptly inactivated to favor catabolism and growth arrest. Mechanistically, mTOR phosphorylates its substrates S6 kinase 1 and eIF4E-binding protein 1 to regulate mRNA translation initiation and progression, thus controlling the rate of protein synthesis.93 Hence, mTOR is implicated in diseases showing growth deregulation and metabolic compromise, such as cancer, diabetes and obesity94 and is a master regulator of senescence and aging in several animal models, such as yeast,95, 96, 97, 98 worms,99 flies100 and mice,101 where mTOR inhibition has been proved to prevent the expression of some senescent markers.102 Overall, many findings suggest that sustained mTOR signaling promotes cell and tissue aging, fostering the idea that inhibition of mTOR may increase longevity. From yeast and Caenorhabditis elegans and up to mice and primates, one of the most effective methods in prolonging lifespan is caloric restriction (CR),103 achieved decreasing caloric intake, without malnutrition. Importantly, mTOR is necessary for the CR beneficial effect and CR fails to extend lifespan in organisms where mTOR signaling has been reduced.104 Moreover, in Drosophila melanogaster, inhibition of mTOR during CR results in selective increased translation of components of the mitochondrial electron transport chain mediated by increased activation of eIF4E-binding protein 1. This selective upregulation leads to improved mitochondrial respiration, decreased ROS production and results in reduced ROS-dependent senescence and prolonged lifespan.105 Strikingly, the drug rapamycin, a chemical inhibitor of mTOR, has been recently shown to prolong lifespan in mammals.101

Active mTOR signaling promotes tumor growth and malignancy and, to some extent, mTOR partners behave like oncogenes.106, 107, 108, 109, 110 Thus, even though it is normally related to cellular growth, mTOR activity reinforces certain types of senescence,.111, 112, 113 In this regard, it is of great interest that overexpression of the GTPase protein mTOR-activator Ras homolog enriched in brain (Rheb) triggers senescence in vivo and in vitro in an mTOR-dependent fashion.111 Similar results were described upon in vivo overexpression of the mTOR downstream target eIF4E.114 Moreover, the ability of mTOR to promote cell growth seems to be pivotal to the establishment of senescence in cell-cycle-arrested cells. Indeed, expression of p21 induces senescence when mTOR is active, but it promotes quiescence when cells are serum starved (that is, mTOR is inactive) or upon pharmacological inhibition of mTOR by rapamycin.102, 115 This may have important implications in p53-induced senescence as detailed below. Nonetheless, this pro-senescence function of mTOR does not apply universally: DNA-damage-induced senescence seems refractory to mTOR inhibition,102 whereas in Ras-driven OIS dampening of mTOR signaling has been reported116 (see chapter p53 and autophagy). Moreover, mTOR promotes senescence via autophagy inhibition, by decreasing lysosomal degradation of intracellular components. Activated by nutrients, mTOR inhibits autophagy, a process that may contribute to mitochondrial dysfunction ER stress and senescence. Indeed, autophagy seems to be required for the senescence response116, 117, 118 (Figure 2).

Recent evidence indicates that p53 can also prevent cell growth, interacting with the mTOR pathway. Interestingly, p53 inhibits mTOR signaling through different ways.119 In fact, p53-regulated sestrins repress mTOR activity directly.120 In addition, p53 triggers expression of the AMP-activated protein kinase (AMPK), which, in turn, inactivates mTOR.121, 122 Finally, p53 upregulates PTEN, an inhibitor of the PI3K pathway, which is an upstream-positive regulator of TOR.

Lately, mTOR regulation by p53 has been implicated in a paradoxical antisenescence role of p53. Induction of p21 allows the establishment of an irreversible senescent arrest. Nonetheless, further accumulation of transcriptional-competent (but even unphosphorylated) p53 triggers inhibition of mTOR and switches cell status to a reversible cell-cycle arrest.14, 123 Unfortunately, the p53-target(s) responsible for this phenotype is yet unidentified, but the ability of p53 to induce cell-cycle arrest and inhibiting mTOR simultaneously could help explaining why moderate increases of p53 activity protects from cancer and simultaneously prolongs lifespan. In addition, these data support our view that p53-mediated senescence is not simply an on–off switch mediated by p21 induction, but it is a complex cellular phenotype that can be fine tuned by regulation of several additional targets and pathways.

p53 and autophagy

Autophagy is an evolutionary conserved self-eating mechanism by which cellular cytoplasmic portions and organelles are delivered to the lysosome for degradation. Degraded products are then recycled for energy production or other metabolic processes, which explains why autophagy is engaged in conditions of nutrient deprivation.124 An additional role for the autophagic process is the removal of damaged macromolecules and dysfunctional mitochondria, avoiding the build-up of damage. As such, autophagy is cytoprotective and can modulate aging and influence cancer survival.125, 126, 127

The longevity pathways interact with the autophagic process to regulate diverse cellular functions, including growth, differentiation, response to nutrient deprivation, oxidative stress, cell death, as well as macromolecule and organelle turnover. Indeed, mutations in genes that promote autophagy reduce lifespan in C. elegans, D. melanogaster and yeast.125, 128, 129, 130, 131 Moreover, CR induces autophagy via repression of the mTOR signaling, and autophagy induction is essential for the anti-aging outcome of reduced caloric intake.132, 133

On the other hand, the role of autophagy in cancer is more debatable.127, 134, 135, 136 Robust engagement of autophagy in tumor areas deprived of blood and nutrient supplies promotes survival of cancer cells, suggesting an ‘oncogenic’ role for autophagy, and several studies have proved that engagement of autophagy protects cancer cell from chemotherapy.137, 138, 139, 140, 141, 142, 143, 144, 145 Conversely, allelic disruption of some autophagic genes predisposes to tumor development, indicating that autophagy may be required to repress tumor onset.146, 147, 148, 149, 150 As far as senescence is concerned, autophagy acts as an effector mechanism during OIS.116 In fact, autophagy is engaged during OIS in a PI3k-mTOR-dependent fashion and its inhibition delays the onset of the senescent phenotype.116

p53 has a dual function in the control of autophagy: it can either activate or repress autophagy.49, 151, 152, 153 On the one hand, nuclear p53 can induce autophagy through transcriptional upregulation of targets such as AMPK, PTEN and sestrins that activate autophagy mainly through inhibition of mTOR. Another pivotal p53-target and positive regulator of autophagy is damage-regulated autophagy modulator, which codes for a lysosomal protein. In response to p53 activation, damage-regulated autophagy modulator is upregulated and elicits autophagy that is necessary to mediate p53-dependent cell death. On the other hand, cytoplasmic p53 represses autophagic flux through a substantially unknown mechanism. Kroemer’s group showed that loss of p53 activity can enhance autophagy and that cytoplasmic, not nuclear, p53 is responsible for autophagy inhibition. Importantly, in this context, inducers of autophagy, such as starvation or rapamycin, induce degradation of p53 that is necessary for autophagy induction.151 Although the physiological implications of p53-regulated autophagy are unknown with regard to senescence induction, there is evidence of their involvement in the regulation of lifespan. Indeed, knockdown of the C. elegans p53 ortholog Cep-1 increases lifespan, a phenotype abrogated by inhibition of autophagy.154

p53 and ROS

As aforementioned, ROS or, more accurately, ROS-mediated damage have been extensively implicated in the induction of cellular senescence and in the onset of aging disorders. p53 shows a Janus role, dictated by its dual capacity to inhibit or promote senescence, by regulating ROS levels.14, 42, 155 Indeed, increasing evidence suggests that transcriptional regulation of antioxidant genes (including mitochondrial superoxide dismutase 2, glutathione peroxidase 1 and mammalian sestrin homologs 1 and 2) accounts for p53’s ability to repress senescence by dampening intracellular ROS levels.156, 157, 158, 159, 160 On the other hand, in cells sensitive to p53-mediated apoptosis, DNA-damage-activated p53 elicits a spike in intracellular ROS content, resulting in cell death or senescence.42, 155, 161, 162 The p53-dependent ROS generation may well represent a crucial event for senescence regulation, but its dual regulation of oxidative metabolism may confer to p53 a double-edged role in the senescence process. As far as aging is concerned, the free radical theory of aging states that ROS-mediated damage has a direct detrimental effect on animal well-being.38 Hence, p53 may counteract aging by mitigating the oxidative burden, as suggested by reduced oxidative damage in long-lived super-arf/p53 mice.74 However, it is unclear whether induction of ROS by p53 in response to stressors is involved in aging.

p53 and mitochondria

Mitochondria have been linked to aging, neurodegeneration163, 164, 165 and cancer.166 As stated, according to the free radical theory of aging, ROS-mediated damage to cellular components is the driving force behind aging.35 As mitochondria are the prime source of ROS, they are as well the main targets of ROS-mediated damage, a hypothesis known as ‘mitochondrial theory of aging’. Impaired mitochondrial activity and the resulting imbalance in oxidative and energetic metabolism can indeed severely affect lifespan and negatively impact on aging.167 Study of telomerase-deficient animals has unveiled a link between p53, mitochondria and aging. Telomerase maintains the stability of telomeres, the nucleoprotein complexes responsible for the genomic integrity of chromosomal ends. Eroded telomeric ends trigger widespread DNA damage, which activates p53 and results in age-related disorders.24, 25 Importantly, depletion of p53 ameliorates the age-related degeneration in telomerase-deficient animals, partially abolishing p53-mediated cell death.28 Intriguingly, upon telomere dysfunction, active p53 represses expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α/β). PGC proteins regulate mitochondrial physiology and energetic metabolism (Figure 3). Their repression decreases mitochondrial biogenesis, reduces oxygen consumption and increases ROS levels.168 These findings bridge DNA damage, mitochondria and aging, and prove that p53 regulation of mitochondrial respiration is likely to affect animal longevity. Intriguingly, basal p53 activity is necessary for maintenance of mitochondrial function. Indeed, p53 promotes the expression of synthesis of cytochrome c oxidase 2, a component of the complex IV of the electron transport chain. p53 null tissues and cells have reduced complex IV activity resulting in impaired oxygen consumption. However, whether this has a role in aging or senescence has not been investigated yet.

Figure 3
figure3

p53 regulates mitochondrial function. Mitochondria are pivotal regulators of aging and accumulating evidences link them to cellular senescence. In unstressed cells, p53 sustains mitochondrial respiration promoting the transcription of the nuclear-encoded mitochondrial protein synthesis of cytochrome c oxidase 2 (a). Conversely, stress-activated p53 (for example, consequently to telomere erosion) represses PGC1a, a positive regulator of mitochondrial function and biogenesis, resulting in impaired mitochondrial respiration and bioenergetic, which has been directly implicated in p53-mediated regulation of animal lifespan (b). In addition, potentially, p53 could affect mitochondria indirectly, through regulation of autophagy. Autophagy of mitochondria, or mitophagy, is essential for the removal of damaged organelles and, hence, the preservation of an efficient pool of healthy mitochondria. Nuclear p53 activates autophagy, whereas cytoplasmic p53 inhibits it. Whether this regulations affect mitochondria and, generally, their physiological implication in aging and senescence still awaits investigation (c,d).

Intriguingly, mTOR signaling has been reported to sustain respiration in human cells,169 whereas autophagy of mitochondria, or mitophagy, removes damage organelles and helps maintain a healthy pool of mitochondria.170, 171 Hence, the ability of p53 to inhibit both mTOR and its dual regulation of autophagy may well be implicated in regulation of mitochondrial function during senescence or aging, a possibility that needs further investigation.

p53 and sirtuins

The crosstalk between p53 and Sirt1 represents a crucial point of regulation of p53 signaling, implicated in many biological processes such as senescence. Sirt1 belongs to a family of evolutionary conserved NAD+-dependent protein deacetylase, classified as class III histone deacetylase, able to deacetylate target histone and non-histone proteins, and thus participates in the regulation of chromatin structure and of DNA accessibility for processing and repair, as well as in transcriptional control networks via deacetylation of transcription factors and cofactors.58, 172, 173, 174, 175, 176, 177, 178, 179 SIRT1 is necessary for the establishment of senescence,180, 181 and SIRT1 is strongly downregulated in senescent cells. A major substrate for SIRT1 is p53, and the deacetylation of p53 regulates cell cycle, cellular senescence and stress resistance in various cell types. Deacetylation inhibits p53’s ability to transcriptionally activate some, but not all, target genes—including those involved in apoptosis, proliferation, ROS production and presumably also senescence.58, 182, 183 Following DNA damage, SIRT1 relocalizes from its constitutive loci to sites of DNA damage where it promotes DNA repair and hence genomic stability. Thus, both SIRT1 and p53 are chromatin/DNA responders that help maintain genomic stability and are coordinated so that SIRT1 favors repair and survival, while p53 elicits programmed removal of overly damaged cells via apoptosis. The presence of a chronic DDR (as may be seen in cancer cells), which is linked to the induction of senescence, can directly increase p53 acetylation by promoting the interaction with the acetyl transferases CBP/p300.184 Acetylation of p53 is also seen to be important during Ras-induced or replicative senescence, where it is antagonized by SIRT1.180, 181, 185, 186 In keeping with this, cells harboring p53 with acetyl-mimicking mutations of the last seven lysine residues have an accelerated entry into senescence and are very resistant to senescence bypass,187 although the cell-cycle arrest response in these cells remains normal. Conversely, mutations that abolish acetylation of the lysine residues located in the DNA-binding domain fails to establish replicative as well as OIS.188 Thus, these data strongly suggest that deacetylation of p53 by Sirt1 impedes the induction of senescence. Whether this is relevant in tumor formation is unclear. Indeed, SIRT1-mediated repression of p53 activity supports the idea that SIRT1 could be oncogenic. However, several mouse models proved that SIRT1 acts as a tumor suppressor reducing cancer incidence even in p53 heterozygous mice.189, 190, 191 Thus, the physiological meaning of SIRT1-mediated deacetylation of p53 remains to be elucidated.

SIRT1 was initially identified as a ‘longevity’ gene in C. elegans,192 yeast193 and Drosophila,194 findings that spurred research in mammalian models. The idea that SIRT1 is necessary to prolong animal lifespan has been heavily questioned.195 Nonetheless, mice-overexpressing SIRT1 have a reduced incidence of age-related metabolic disorders, including diabetes, liver steatosis and196 cancer. In other words, it is now evident that SIRT1 is not necessary to live longer, but to live healthier. Currently, it is unclear whether p53 is required for the metabolic function of SIRT1.

P53-induced senescence in cancer therapy

The cancer cell phenotype is characterized by sustained proliferative signaling, alteration of cellular homeostasis and metabolism.197, 198 Senescence is a robust physiological antitumor response that is engaged by tissues to counteract oncogenic insults. Accumulating evidence of its involvement in the onset and therapeutic response in humans has spurred considerable efforts towards its therapeutic exploitation.176, 199 Indeed, therapy-induced senescence is an emerging appealing approach to halt tumor growth; several agents are reported to induce senescence by acting on different pathways, as demonstrated in vitro and in human tumors and in tumor models (Table 1). The DDR entails senescence as an anticancer mechanism; indeed, many drugs induce senescence following DNA damage. In OIS, the genetic lesions that initiate tumorigenesis (for example, RAS overactivation) promote senescence at the early stage of cellular transformation. For transformation to occur, additional genetic modifications are necessary to overcome senescence.17, 77, 82, 200, 201 Therefore, designing innovative therapeutic approaches to trigger tumor regression re-activating senescence programs and effectors is appealing. In this regard, modulation of p53 activity may be appropriate.56, 57, 202, 203, 204, 205, 206, 207 Recent findings have demonstrated that reactivation of p53 in tumors elicits a robust tumor regression mediated by induction of senescence.203, 204 These studies boosted the long-standing efforts to develop drugs able to reactivate p53 in tumors-bearing null or mutant p53.59, 73, 186, 205, 208, 209, 210, 211 Nonetheless, the efficiency of p53-mediated tumor clearance is also stage-specific and dependent on the overall ‘oncogenic’ burden. Indeed, using a mouse model of K-Ras-driven lung cancer, two different research groups demonstrated that p53 reactivation is efficient only in advanced cancers characterized by sustain Ras-Raf-Mef-Erk signaling. In addition, in the same system, p53 tumor suppressor activity does rely on co-expression of p19ARF. Although these results cast doubt on the potential therapeutic benefit of p53 restoration in cancer therapy, they also unveil an interesting parallelism between p53 tumor suppressive function and regulation of aging. Indeed, in the super-arf/p53 mouse model, increased expression of p19 is essential to prolong lifespan, whereas increased dosage of p53 alone does not suffice.212, 213 These findings highlight the existence of a p19–p53 axis, where ARF expression seems to be necessary to fully engage p53 activity.

Table 1 Table reports anticancer drugs currently undergoing clinical trials (source www.clinicaltrial.gov), which induce cellular senescence in cancer cell lines and tumors

The phytoalexin resveratrol is known to possess a variety of cancer-preventive, therapeutic and chemosensitizing properties. It has been reported that chronic treatment with resveratrol in a subapoptotic concentration induces senescence-like growth arrest in tumor cells (Table 1). Resveratrol has proved to act by increasing the level of ROS and induce a p21–p53-dependent senescence.214 This anticancer property of resveratrol is particularly intriguing on the light of its debated role in regulating aging and sirtuin function. Because of the debate on the issue, we refer to other reviews for details,125, 215 but in summary, there is evidence that resveratrol may improve healthy aging, especially by counteracting obesity and diabetes, and that this could be mediated, at least partially, by activation of Sirt1 and induction of autophagy. Hence, resveratrol is able to suppress tumor growth, while improving organismal metabolism.

A promising target for senescence induction in cancer cells is the enzyme telomerase. Findings have demonstrated that short telomeres induce senescence, limiting tumor suppression.216, 217 The evidence that senescence induced by telomere shortening is an in vivo tumor suppression process comes from studies in mTERC−/− mice, in which shortened telomeres decrease tumorigenesis when block of apoptosis is due to p53-mutant R172P expression.218 Furthermore, the DDR activated by telomere dysfunction induces the ATM/ATR and Chk1/Chk2 activation, which consequently phosphorylates and stabilizes p53.29

Evidence that deletion of key regulators of senescence, for example, p53, p27, PRAK or Arf, induces tumor progression and senescence block, connect the loss of senescence to tumor transformation.82, 219, 220, 221, 222 Eighty to ninety percentage of human cancers seem to be associated with unlimited proliferation due to activation of telomerase.223, 224 Therefore, the inhibition of telomerase could be a promising therapeutic target for cancer, because telomere shortening induces senescence in cancer cells21 and this kind of approach could offer the additional advantage to specifically target cancer cells, characterized by telomerase expression, unlike normal cells.

A family matter: P63 and P73 in senescence and aging

Two others p53 homologs of p53 have been characterized over the past two decades: p63 and p73.225 Like p53, both proteins contain three domains: a N-terminal transactivation domain, a DNA-binding domain and an oligomerization domain responsible for tetramerization. In addition, the use of different promoters and alternative splicing results in the expression of multiple isoforms. Briefly, alternative splicing at the 3′-end of the primary transcript originates three isoforms in p63 and at least seven in p73, some of which contain an additional C-terminal protein/protein interaction domain, the sterile alpha motif, absent in p53.225 Although several studies have attempted to dissect specific functions of these proteins, at present clear-cut roles for these different variants have not been attributed. As mentioned, the use of alternative promoters generates two additional N-terminal variants. An upstream promoter transcribed longer, transcriptionally competent isoforms containing a transactivation domain (TAp63 and TAp73), whereas an internal downstream promoter originates shorter isoforms that lack the transactivation domain (ΔNp63 and ΔNp73) and are thought to act as dominant negatives.226

Both TAp63 and TAp73 are activated in response to DNA damage by the non-receptor tyrosine kinase c-Abl227, 228, 229, 230, 231, 232 and act as proapoptotic molecules.233, 234 Although they are involved in cancer and chemotherapy response,226, 235 p73 has a major role in regulation of inflammation236, 237 and brain development through several mechanisms,238, 239 including preservation of neural stem cells240, 241, 242 and, importantly, its depletion predisposes to age-related neurodegeneration in mouse models.243, 244, 245 In addition, TAp73 has been involved in the preservation of genomic stability and fertility, and is important for accurate mitotic and meiotic division.64, 246, 247, 248 p63’s role in cancer onset and metastatic spread has been widely investigated,249, 250, 251 but it also has a fundamental role in epithelial development and maintenance of the epithelial stem cell reservoir252, 253, 254, 255, 256, 257, 258 and protects the female germ line against DNA damage.259 Nonetheless, like their sibling p53, both genes have a role in senescence and aging. Indeed, the recent development of several N-terminal selective-knockout (KO) mouse models has helped understand the involvement of these isoforms in complex biological processes, such as senescence and aging. p63 null mice (that is, lacking all isoforms) show a very severe phenotype and die shortly after birth,260, 261 although long-term analysis of heterozygous mice allowed detection of premature aging.262 These findings were strengthened by the development of inducible TAp63-KO mice.263 In this setting, depletion of p63 in the epithelial compartment was sufficient to accelerate aging, which correlated with accumulation of senescence markers in vivo and in isolated keratinocytes. In particular, the establishment of the senescent status relies on PML, a known mediator of senescence.263, 264, 265 Further insights into p63 regulation of the aging process were provided by development of TAp63 isoform-specific KO. Flores and colleagues showed that absence of TAp63 has severe effects and results in skin ulceration, premature aging and reduced lifespan. Interestingly, this correlates with strong cellular senescence triggered by genomic instability, which is responsible for the loss of the epithelial stem cell repertoire.266, 267 Although these findings suggest that lack of p63 induces senescence, other reports have shown that TAp63 mediates the induction of OIS in keratinocytes, similarly and independently of p53.268 Hence, it appears that p63, especially its transcriptionally competent isoforms, share a Janus role with p53: their activation in response to oncogenic stress is necessary to halt transformation via senescence, but their absence compromises the stem cell reservoir and promotes aging. Nonetheless, to fully address the role of p63 in senescence and aging, it is necessary to take into account the activity of the N-terminal truncated proteins. Indeed ΔNp63 isoforms are by far the most abundant isoforms expressed in epithelial cells. They have been consistently reported to support the maintenance of the stem cell compartment of the skin and to antagonize the induction of replicative senescence.255, 269 Moreover, ΔNp63 downregulation by oncogenic K-Ras is necessary for establishment of OIS and tumor prevention in keratinocytes.270 Unfortunately, it is still unclear to what extent these isoforms affect aging, and data on isoform-specific KO are eagerly awaited.

p73 has been linked to OIS and in fact expression of ΔNp73 has been reported to bypass Ras-induced senescence allowing cellular transformation to occur.271 Moreover, oncogenic Ras promotes a switch from TAp73 to ΔNp73 expression to sustain transformation. Indeed, transformed mouse fibroblasts, lacking ΔNp73, fails to form tumors in nude mice because of ensuing senescence.244

Recently, by mean of isoform-specific KO models,247 we have demonstrated that mice lacking TAp73 show an aggravation of several aging-related parameters (hunchback, cataract, alopecia and skin thinning among others).34 In addition, fibroblasts isolated from null embryos were more susceptible to oxidative stress and underwent senescence at higher rate than wild-type counterparts. In the quest for a mechanism underlining the observed phenotypes, we showed that TAp73 regulates expression of a cytochrome c oxidase 4 subunit 1 (Cox4i1), a protein essential for assembly of fully functional mitochondrial complex 4. Consequently, lack of TAp73 impaired activity of the complex 4 of the electron transport chain and decreased oxygen consumption both in vitro and in vivo, similarly to depletion of p53. This resulted in reduced ATP cellular content and increased cellular ROS and oxygen sensitivity. Hence, we proposed that the mitochondrial and metabolic dysfunction triggered by depletion of TAp73 underlined the accelerated aging in KO animals.34

In summary, regulation of senescence and aging are shared functions of the p53-family members.

Concluding remarks

The molecular mechanisms underlying the senescence pathway are becoming increasingly topical owing to its role in tumor suppression, giving great relevance for its potential exploitation in cancer therapy. Although these molecular mechanisms are only partially elucidated and are currently under intense investigation, it is evident that p53 has a key role in its regulation. Indeed, p53 can modulate senescence at different levels. Surprisingly, p53 seems to show a dual effect, promoting or in same case inhibiting the senescence program. This dual effect of p53 is still unclear; a possible explanation can be the dependence on the degree and type of stress or the cellular milieu where p53 is active. Indeed, mild stress can induce p53 to repair the cell and activate antioxidant mechanisms, while more severe stress leads p53 to induce apoptosis and senescence, via ROS generation. In the context of cancer therapy, the ability of p53 to regulate senescence is emerging as a promising and alternative way to eliminate cancerous cells, because p53-signaling pathways can be manipulated at several steps to stimulate senescence. Beyond its antitumor ability, senescence is emerging as a casual factor in aging.11 Presently, while it is clear that modulation of p53 activity affects lifespan, the contribution of senescence to this function needs further investigation. In a recent mouse model of hyperactive p53 and consequent aggravation of aging disorders, the concomitant removal of the proapoptotic p53 target PUMA suffices to rescue the stem cell repertoire and increase the lifespan of mutant mice. This suggests that apoptosis may be critical to p53-induced aging. But, on the other hand, it does not exclude an additional role for senescence. In particular, apoptosis can explain the defect in tissues subject to extended self-renewal (for example, bone marrow or gut), but it is unclear whether it could explain the aging-related degeneration that accompanies quiescent tissues (such as liver or brain).272 In this context, senescence may have a more critical role, which would be worth investigating.

Mechanistically, we have proposed several mechanisms that are at the crossroads between senescence and aging: ROS scavenging and generation, mitochondrial function, mTOR signaling and autophagy. Importantly, these biological processes are intimately linked: mTOR positively regulates respiration in mammalian cells169, 273 and renders cancer cells addicted to mitochondrial activity.274 Moreover, it inhibits autophagy, and autophagy of mitochondria (a process known as mitophagy) is essential to remove dysfunctional mitochondria, whose accumulation would result in increased ROS production and reduced energy efficiency. Activation of autophagy depends on ROS, while autophagy dampens intracellular ROS build-up.38, 275, 276, 277 Intriguingly, SIRT1-mediated deacetylation of PGC-1α is required for its activation of mitochondrial biogenesis and gluconeogenesis,278 thus antagonizing p53-negative regulation of PGC-1α. In other words, p53 is controlling a network of tightly connected biological processes that impinge on senescence and aging. Future efforts are necessary to fully address how p53 regulates these processes, how they interrelate in the context of p53 regulation and their overall relevance to cancer and aging.

Finally, a growing body of evidence points to mitochondria as crucial factors in aging and senescence. Indeed, dysfunctional mitochondrial function accompanies OIS, and several mouse model of dysfunctional mitochondria show worsening of the aging phenotype.168, 279, 280, 281, 282, 283, 284, 285 Strikingly, overexpression of the scavenging enzyme catalase exerts negligible effects on longevity if targeted to the peroxisomes or the nuclei, but extends median lifespan by 20% when targeted to the mitochondria,286 and a recent study demonstrated that this genetic manipulation prevents the age-associated decline in mitochondrial activity.281 Our recent data on TAp73-selective KO and the findings of Ronald DePinho’ s Laboratory on the p53-PGC1α axis both support a model whereby depletion or hyperactivation of the p53 family members leads to aging through impaired mitochondrial function and metabolic compromise (Figure 4).272 These findings also explain the aging decline of quiescent organs (such as liver) that do not depend on a strong stem cell pool (such as the haematopoietic system or skin) and thereby are less susceptible to apoptosis mediated by DNA damage and p53 activation. Future studies to thoroughly address the mitochondrial function and metabolic profile of long-lived mouse models such as super-arf/p53 or short-lived p53-knock-in mice are desirable. Similarly, these recent studies urge immediate work to investigate whether p63 shares with its siblings the ability to regulate oxidative metabolism, making it definitively a family matter. Intriguingly, a recent paper demonstrated that TAp63 upregulates expression of SIRT1 and AMPKα2 (one of the subunit of AMPK). Although the authors do not investigate mitochondrial function in detail, they demonstrate that TAp63 null mice have reduced activity of SIRT1 and AMPK in vivo, which renders these animals extremely susceptible to obesity and insulin resistance following high-fat diet regimen.287 Although further studies are necessary, it is becoming increasingly evident that regulation of energetic metabolism is a main function of the p53 family of genes with essential consequences on animal lifespan and well-being.

Figure 4
figure4

The unified theory of aging and the p53 family. Recent findings suggest that p53 regulates mitochondrial function in both stress and unstressed conditions. In unstressed cells, it regulates expression of synthesis of cytochrome c oxidase 2 (SCO2) and help sustaining and oxidative energy production. In response to stress, such as telomere erosion, p53 is activated in response to DNA damage and directly repress the expression of PGC1a/b protein, causing reduction in mitochondrial mass and function and increasing ROS content. Similar results were described for p73: deletion of the TA isoforms worsen aging in mice and results in increased cellular ROS levels, oxidative damage and senescence triggered by mitochondrial dysfunction. In this case, the target responsible, at least partially, for the described phenotype is cytochrome c oxidase 4 subunit 1 Cox4i1. Unfortunately, data are still missing with regards to p63 and it is not clear whether, upon stress, activated p63 and p73 are able to regulate mitochondrial function similarly to p53. Further studies aim to investigate these possibilities are eagerly awaited.

Abbreviations

DDR:

DNA damage response

ROS:

reactive oxygen species.

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Rufini, A., Tucci, P., Celardo, I. et al. Senescence and aging: the critical roles of p53. Oncogene 32, 5129–5143 (2013). https://doi.org/10.1038/onc.2012.640

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Keywords

  • senescence
  • aging
  • p53
  • mTOR
  • mitochondria
  • ROS

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